Abstract

Recurrent hypoglycemia is the most feared complication of intensive insulin therapy for type 1 diabetes. Study of the cognitive
impact of recurrent hypoglycemia in humans has been hampered by difficulty in controlling for prior glycemic history and diabetes
status; there have been no prospective studies. We used a rat model of recurrent hypoglycemia with hypoglycemia for 3 h, once
weekly, from 1 month of age. At 4, 8, and 12 months of age, cohorts were tested on a hippocampally dependent spatial memory
task, during which hippocampal extracellular fluid (ECF) glucose and lactate were measured using microdialysis. At 4 months,
recurrent hypoglycemia improved euglycemic task performance (76 ± 4 vs. 64 ± 3% for controls) and reversed the task-associated
dip in ECF glucose seen in controls. However, recurrent hypoglycemia impaired performance in animals tested when hypoglycemic
(45 ± 4 vs. 55 ± 2%). Recurrent hypoglycemia preserved euglycemic task performance across age: at 12 months, both task performance
(62%) and ECF glucose changes in euglycemic recurrently hypoglycemic animals resembled those of 4-month-old control animals,
whereas control animals’ performance deteriorated to chance (44%) by 8 months. At 12 months, hippocampal slice physiology
was assessed, with results paralleling the cognitive findings: slices from recurrently hypoglycemic rats showed improved γ-aminobutyric
acid (GABA)ergic inhibition at euglycemia but much greater loss of this tone at low bath glucose. Our data show that moderate
weekly hypoglycemia prevented age-related decline in hippocampally cognitive function and cognitive metabolism, at least when
euglycemic. The impact of recurrent hypoglycemia on cognition is multifaceted and includes both metabolic and electrophysiological
components.